1. Field of the Invention
The present invention relates to compounds that modulate/activate the human thrombopoietin receptor. Suitably, the method relates to methods of treating thrombocytopenia by administration of 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-(monoethanolamine) salt, (hereinafter the bis-(monoethanolamine) salt is Compound A;
which is a compound is represented by Structure I:

and Compound B refers to the corresponding salt free compound or a pharmaceutically acceptable salt thereof).
2. Description of the Related Art
Thrombopoietin (TPO), also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor, is a glycoprotein that has been shown to be involved in production of platelets. See e.g., Wendling, F., et. al., Biotherapy 10 (4):269-77 (1998); Kuter D. J. et al., The Oncologist, 1:98-106 (1996); Metcalf, Nature 369: 519-520 (1994). TPO has been cloned and its amino acid sequence and the cDNA sequence encoding it have been described. See e.g., U.S. Pat. No. 5,766,581; Kuter, D. J. et al., Proc. Natl. Acad. Sci., 91:11104-11108 (1994); de Sauvage F. V., et al., Nature, 369: 533-538 (1994); Lok, S. et al., Nature 369:565-568 (1994); Wending, F. et al., Nature, 369: 571-574 (1994).
In certain instances, TPO activity results from binding of TPO to the TPO receptor (also called MPL). The TPO receptor has been cloned and its amino acid sequence has been described. See e.g., Vigon et al., Proc. Natl. Acad. Sci., 89:5640-5644 (1992).
In certain instances, TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404-409 (1997). For example, patients undergoing certain chemotherapies, including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, or exposure to high levels of radiation may have reduced platelet levels. Treating such patients with a TPO agonist compound increases platelet levels. In certain instances, selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
Generally, an increase in platelet count to a therapeutically beneficial level in a subject occurs after a prolonged period of time during a treatment regimen. For example, the increase in platelet count to a therapeutically beneficial level in a subject using a maintenance dose of a TPO modulator may occur after a week of treatment.
The standard dosing amount for the compound of the invention is generally considered to align with the amounts disclosed in International Application No. PCT/US07/074918, having an International filing date of Aug. 1, 2007; International Publication Number WO 2008/136843 and an International Publication date of Nov. 13, 2008, in which the highest dose prepared is a 100 mg tablet. However, the amounts described in PCT/US07/074918, specifically a 50 mg, 75 mg and 100 mg dose, were found to not meet the target platelet improvement counts in patients receiving carboplatin/paclitaxel as presented at the Multinational Association of Supportive Cancer Care—Annual Meeting, 2007 in a poster titled: Efficacy and safety of eltrombopag, a novel, oral platelet growth factor on platelet counts in patients with cancer receiving carboplatin/paclitaxel chemotherapy—by Baranwal et al.
It would be useful to provide a novel therapy which provides more effective and/or enhanced treatment using 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof.